Method and apparatus for stopping and dissolving acoustically active particles in fluid

ABSTRACT

The invention presents a method for selectively slowing the motion of acoustically active particles immersed in a flowing fluid, eventually stopping their motion, holding them in place by pushing them against a surface or against the flow of said flowing fluid, and/or breaking up said acoustically active particles into smaller particles and/or dissolving them. The invention also relates to various systems that utilize this method.

FIELD OF THE INVENTION

The present invention relates to the handling of acoustically activeparticles in a fluid. More specifically the present invention relates toa method and apparatus using ultrasound energy to selectively stop,break apart, shrink, and dissolve acoustically active particles immersedin a flowing fluid.

BACKGROUND OF THE INVENTION

Acoustically active particles, e.g. gas filled bubbles or liquiddroplets often are found immersed in a stationary or flowing fluid thatis confined within some form of vessel (container, tube etc.). Theseparticles are often undesirable and in many cases are actually harmful,interfering with the flow and/or function of the fluid. In suchsituations, there is a need to stop their being carried along with theflowing fluid and/or to reduce their size and/or, in some instances, toentirely dissolve them in the surrounding fluid in order to eliminatetheir potential to do damage.

Bubbles (drops) can be immersed in a fluid in a vessel by twomechanisms:

-   -   1. They can be introduced into the fluid from either an outside        source (for example: via injection), or as gas released from        within a closed container that has been placed in the fluid.    -   2. They can be formed inside the fluid itself (intra-fluid,        intra-vessel) due to pressure changes. Fast intensive injection,        turbulent fluid flow (stream), rapid changes in the vessel's        dimensions, fluid flow speed, and other causes can all bring        about pressure changes, which result in formation of bubbles.

Situations in which it is either necessary or desirable to selectivelyarrest and dissolve acoustically active particles in a fluid occur, forexample, in the food processing industry; fluid transport throughpipelines; the flow of fuel, oil, or coolants in machinery or engines;the paint manufacturing industry; etc. The field in which the problem isarguably the most critical and in which a great amount of resources havebeen invested in attempting to alleviate the problem is the field ofmedicine. It is from this field that the examples below are drawn inorder to describe both the problems created by the presence of thebubbles and the state of the prior art.

Air bubbles or other types of acoustically active particles areintroduced into blood vessels during many different forms of invasiveprocedures. Such procedures include: open heart surgeries, hyperbaricstherapy, dialysis treatments (including but not limiting, hemodialysisand hemodiafiltration), minimally invasive stent placement procedures inthe cardiac arteries, interventional radiology procedures involvingcontrast media injection to the cardiovascular system including thecerebral vasculature, and the aorta, X-ray angiographies underfluoroscopy, CT and MRI scans, and during intensive IV (intra-venous)infusions.

Two types of central nervous system (brain) deficits may occur followingthe above mentioned invasive procedures resulting from the introductionof bubbles into the arterial blood vessels supplying the brain: 1.)focal deficits (stroke) and 2) diffuse cerebral dysfunction,encephalopathy and cognitive damage. Most often these deficits arerevealed in the form of subtle mental damage, mild intellectualimpairment, confusion or agitation, memory loss, personality changes ordepression. When the damage is severe, loss of consciousness, coma, andeven death may occur. The parameters which affect the extent of thebrain damage due to the bubbles include: their size, the total airvolume occupied by the bubbles, and the load (the volume of the bubblesin a given time period). Current techniques for stopping the formationand advancement of the bubbles and air emboli comprise changing thebubble oxygenators to membrane oxygenators at the bypass machines inheart surgery and using barrier filter technology, which is limited torelatively large filter pore sizes mainly ranging from 33 to 40 μm. Poresizes in the range of cerebral capillaries (7 μm) and red blood cells (8μm) would improve the filtration of bubbles; but would have a highresistance to flow, would induce more red blood cell trauma, and be apotential source for contamination. Also due to the pressure changesnear the filter, large bubbles condense in front of the filter, passthrough its pores, exit again and advance towards the brain. Even whenusing modern bypass machines, studies show, that bubbles are stillpresent at vessels beyond the filter and at the brain [Richard E. Clark,“Microemboli during coronary artery bypass grafting: Genesis and effecton outcome”, Thorac Cardiovasc Surg, 1995; 109:249-258; Borger, MichaelA. and J Thorac, “Neuropsychologic impairment after coronary bypasssurgery: Effect of gaseous microemboli during perfusionistinterventions”, Cardiovasc Surg, 2001; 121:743-749)].

U.S. Pat. No. 5,811,658 [which is based on the article: Karl Q.Schwartz, “The acoustic filter: An ultrasonic blood filter for theheart-lung machine”, J Thorac Cardiovasc Surg 1992; 104: 1647-53]describes a new acoustic filter which can replace or be added to themechanical filter. According to the method disclosed in this patent,ultrasonic energy is used to divert air bubbles from the mainbloodstream to a different chamber where they can be removed. This typeof filter can prevent only the bubbles formed at the oxygenator fromreaching the blood vessel, but not the following: air bubbles formed atthe aorta where the arterial line injects the oxygenated blood at highpressures; emboli formed due to surgical intervention; and airaccumulated in the heart, which accounts for most of the air emboliduring valve replacement surgeries.

A similar type of device is disclosed in International patentapplication WO01/41655. The devices described in this publicationgenerate ultrasonic waves that are used to direct the flow of thebubbles in the blood stream directing them to alternate paths or tomeans to draw them out of the main flow of the fluid into side tubes orby pushing the bubbles to the middle of the tube, where some of themcoalesce to form bigger bubbles, and then by sucking them out with asyringe tip placed at the middle of the tube. Neither this publicationnor the patent cited above suggests the possibility of stopping bubbles,either from outside sources or those formed intra-vessel, and breakingthem up, to accelerate the process of dissolving them, or dissolvingthem.

Other medical conditions that can be given as examples of situationsrequiring the utmost care in preventing the introduction of gas bubblesinto the blood stream are cerebral and cardiac arterial catheterizationand hemodialysis and hemodiafiltration proceedures.

When performing systemic, cerebral and cardiac arterial catheterizationit is recommended to extract slowly the contrast media saline from thebottle and inject it slowly to the patient. These procedures cannotalways be followed because of the intense and dynamic nature of theseinterventional procedures. Even if the staff pays careful attention tothe formation of bubbles, contrast media must be injected intensely inorder to get good imaging of the vessels.

If a patent foramen ovale (PFO) condition is diagnosed in a patient,then the medical staff is encouraged to pay meticulous attention to theformation of air bubbles in intravenous catheters during operations andprocedures in intensive care units. PFO is present in one out of fourpeople and for most of them the shunt between the right and left atriumis silent; however, even for a mild condition of PFO, increasing theright atrium pressure (for example by taking deep breath) results inpassage of venous blood from the right atrium to the left side. Sourcessuggest that as little as 2 to 3 ml of air passing through the PFO shuntis enough to cause serious brain damage and stroke.

Another very important situation requiring the utmost care in preventingthe introduction of gas bubbles into the blood stream is the problem ofchronic air bubbles during hemodialysis and hemodiafiltration.Currently, there are more than 1,000,000 dialysis patients worldwide.Hemodialysis and hemodiafiltration are beneficial treatments in thefield of renal replacement therapy for patients with end-stage renaldisease. A dialysis patient undergoes more than 150 dialysis treatments,each lasting an average of 3 hours, yearly. During these treatmentsmicrobubbles enter the patient's blood circulatory system and causechronic microemolization in the pulmonary vasculature, which leads tomany different types of pulmonary side-effect damage such as pulmonaryfibrosis and calcification. In patients with a right-to-left shunt(PFO), paradoxical air emboli can occur and microbubbles may reach thecerebral vasculature resulting in slowly evolving cognitive deficits,which are common in patients on long-term hemodialysis [Yu A. S. andLevy E., “Paradoxical cerebal air embolism from a hemodialysis catheter”Am J Kidney Dis 1997; 29: 453-455; Briefel G. R., Regan F., and PetronisJ. D., “Cerebral embolism after mechanical thrombolysis of a clottedhemodialysis access”, Am J Kidney Dis 1999; 34: 341-343].

From the above discussion, it is clear that, especially in cases of PFO,there is an urgent need for a method and apparatus that is able topeffectively prevent the introduction of air bubbles into the bloodstreamduring clinical procedures.

Drug therapy for cancer treatment is another example, also from thefield of medicine, of a situation in which it would be desirable to havean efficient method for stopping the flow and dissolving microparticlesin flowing fluids.

Cancer is the second largest killer in the world. One in three Americanswill eventually develop cancer. These patients are usually treated withsurgery, drug therapy, and radiation therapy with many patients given acombination of therapies. Treatment with anticancer drugs may be givenintravenously (injected into a vein) or by mouth. The drug travelsthrough the bloodstream in order to reach cancer cells located anywherein the body. Chemotherapy can be used as the main treatment for theprimary cancer or to or in cases where the cancer has spread andmetastasized outside of the organ at the time it is diagnosed, orspreads after initial treatments. Neoadjuvant chemotherapy often shrinksthe cancer so that surgery can remove cancers that would otherwise betoo large for complete surgical removal. Chemotherapy is given incycles, with each period of treatment followed by a recovery period. Thetotal course of chemotherapy lasts three to six months depending on theregimens used. People having chemotherapy sometimes become discouragedabout the length of time their treatment is taking or by the harmfulside effects, including fatigue, hair loss, serious heart conditions,nausea and vomiting, loss of appetite, mouth sores, a higher risk ofinfection caused by a destruction of white blood cells, bruising orbleeding after minor cuts and shortness of breath from which theysuffer.

Despite the advances in cancer treatment, there are many areas where theneed for effective chemotherapeutic agents remains significantly unmet:advanced prostate cancer, uterus cancer, liver and renal cancer, coloncancer, lung cancer, brain and breast cancer. A treatment for certaintypes of cancer is hormonal manipulation, which is a non-curativeapproach. Many patients undergo radiation and chemotherapy treatments.In forty five percent (45%) of newly diagnosed cancer patients and inninety percent (90%) of patients receiving chemotherapy, cancers areresistant, to varying degrees, to the chemotherapy.

In order to solve or at least lessen the effect of some of the aboveproblems, great efforts are being made to develop site specific drugs,which allow more precise targeted drug delivery to the tumor site. Inthis technique, chemotherapy drugs are encapsulated in lipid (or othersubstances) microspheres and can be coated with antigens to be morespecific to the cancer cells receptors. The location of the microspheresin the blood stream can be monitored via an ultrasound device and atriggered explosion of the microsphere is possible once the chemotherapyhas been absorbed by phagocytes within the tumor.

In order to increase the effectiveness and accuracy of this method oftreatment, it would be very useful to have an effective method ofslowing, stopping, and accumulating the encapsulated drug at the targetsite, and rapidly dissolving the outer shell both in the intra and extravascular regions, therefore releasing the encapsulated drug. In this waythe drugs would undergo less systemic cycles and have greaterbioavailability in the targeted area. This would result in fewer sideeffects, and increased intake possibility by the targeted cells. Aspecial catheter can be used in order to release the drugs into thearteries for supplying the targeted site and allowing even more accuratedrug delivery.

International patent application WO 02/058530, shows the use of devicesin which drug particles are accelerated and then shot on to the surfaceof the skin. In some embodiments the device is adapted to penetrate theskin before releasing the drug. The disadvantages of this invention arethe need to penetrate healthy tissue with the device in order to reachdeep sites and the particles acceleration process which is carried outinside the device. As opposed to the method disclosed in thispublication, allowing the drugs to taxi independently via the body'svascular system and/or tumor vascular system and accelerating theparticles to the vessel walls without penetrating the skin surface withthe device would be a significantly improved approach to the problem ofdrug delivery, both in concept and technology.

It is therefore a purpose of the present invention to provide a methodfor selectively stopping and/or shrinking and/or dissolving acousticallyactive particles immersed in a flowing fluid.

It is another purpose of the present invention to provide apparatus forselectively stopping and/or shrinking and/or dissolving acousticallyactive particles immersed in a flowing fluid.

It is a further purpose of the present invention to provide a method ofslowing, stopping, and accumulating an encapsulated material immersed ina flowing fluid at a target site, thus enabling efficient uptake ofencapsulated material into the tumor cell.

Further purposes and advantages of this invention will appear as thedescription proceeds.

SUMMARY OF THE INVENTION

In a first aspect, the present invention is directed towards a methodfor selectively slowing the motion of acoustically active particlesimmersed in a flowing fluid, eventually stopping their motion, holdingthem in place by pushing them against a surface or against the flow ofthe flowing fluid, and/or breaking them up into smaller particles and/ordissolving them. the method comprises the following steps:

-   -   (a) exposing said acoustically active particles suspended in        said fluid to ultrasonic waves propagating through said fluid;    -   (b) pushing said particles in the direction of propagation of        the ultrasonic waves by means of the acoustic radiation force        exerted by the waves;    -   (c) slowing and/or stopping the motion of the acoustically        active particles as they enter a friction layer near a surface        or surfaces; and    -   (d) providing an acoustic radiation force having a temporal        waveform to act on the acoustically active particles, thereby        breaking up the ultrasonically active particles into particles        having smaller size and/or causing the particles to dissolve in        the fluid.

The acoustic radiation forces for pushing and for breaking up theparticles can be produced by either the same or separate sources and canbe applied as a superimposition of acoustic radiation forces having twoor more frequencies and or waveforms. The waveforms can be eithercontinuous or pulsating.

The method of the invention can comprise the additional steps of:

-   -   (i) after step (a), aiming the ultrasonic waves towards the        surface of a wall of the vessel containing the fluid or a        surface placed in their path;    -   (ii) after step (b), reducing the speed of the acoustically        active particles, which is equal to that of the fluid        surrounding them as they are progressively pushed into regions        of the fluid closer to the surface; and    -   (iii) after step (c), pushing the acoustically active particles        against the surface by means of the force exerted by the        acoustic radiation, thus creating frictional forces between the        surface and the acoustically active particles which prevent the        movement of the particles and pulsating compressional forces        that cause the acoustically active particles to dissolve in the        fluid.

In another embodiment of the method of the invention, the acousticradiation force for pushing and the acoustic radiation force forbreaking up are aimed in a direction opposite to the direction of flowof the fluid and along the axis of the vessel through which the fluidflows. The acoustic radiation force for pushing and the acousticradiation force for breaking up can be focused.

According to the method of the invention, the acoustic radiation forcefor pushing and/or the acoustic radiation force can be generated upondetection of the acoustically active particles by one or more detectors.The detector can be an ultrasonic detector or an electro-optic detector.The detection can be made by detecting ultrasonic energy emitted by anultrasonic transducer, refracted by the particles, and detected byeither the emitting transducer or another transducer.

The flow of the fluid can be either through a vessel that is open to orsurrounded by an object and hidden from view. Ultrasonic detectors,which detect the flow of fluid through the vessel, can be used to aid indetermining the orientation of the vessel. The vessel can be locatedwithin a human body and can be a blood vessel including a carotidartery.

The surface can comprise one or a plurality of membranes upon whichlarge acoustically active particles break apart into smaller particlesthat pass through the openings in the membranes upon impact. The size ofthe pores in the membranes can be between 0.1 μm to 1 mm. The membranestogether with the ultrasonic propagating field acting on theacoustically active particles act as a semi-permeable membrane whichpermits particles to leave the fluid flow through the pores of themembranes and prevents the particles from reentering the flow. An arrayof open cells can be provided on the side of the membrane surfaceopposite to the flow of the acoustically active particles and whereinafter broken apart particles pass through the pores, they enter thecells thus preventing them from recombining to form particles whosedimensions exceed that of the cells. The pressure exerted onacoustically active particles larger than the pore size of the membranecauses them to deform without breaking apart upon impact with themembrane and slip through the pores, regaining their original shapeafter slipping through the membrane. In one embodiment, the dimensionsof the pores of each succeeding membrane in a plurality of membranesbecome smaller in the direction of the fluid flow. The surface comprisean array of cells arranged in a honeycomb pattern.

In a preferred embodiment of the invention, the acoustically activeparticles comprise an encapsulated material, which can be a drug.

In another aspect the present invention is directed towards anultrasonic system for selectively slowing the motion of acousticallyactive particles immersed in a flowing fluid, eventually stopping theirmotion, holding them in place by pushing them against a surface oragainst the flow of the flowing fluid, and breaking up the acousticallyactive particles into smaller particles and/or dissolving them. Theapparatus comprises:

-   -   (a) a fluid flow path through a vessel;    -   (b) acoustically active gaseous or fluid particles immersed in        the flowing fluid;    -   (c) a surface which creates a friction layer to the fluid that        flows adjacent to it, and can be partially or fully submerged in        the fluid, or may consist of a wall of the vessel or a type of        membrane;    -   (d) Transducing means acoustically connected to the vessel or        submerged in it.

In the system of the invention:

-   -   the transducing means delivers acoustic energy having sufficient        power to accelerate the acoustically active particles towards        the surface where their motion relative to the flowing fluid        ceases and to cause breaking apart of the acoustically active        particles on the surface;    -   the acoustic energy being modulated at the optimal deformation        frequency of the acoustically active particles, thereby causing        safe and selective breakage of the particles into smaller        particles which naturally dissolve faster than large particles;        and    -   the acoustic energy being superimposed by harmonic frequencies        thereby achieving a negative rectified diffusion of substance        from inside the particle to the fluid, or at least lowering the        rectified diffusion particles, thus reducing the risk of jet        streams and cavitations.

In a preferred embodiment of the system of the invention, the surface isa layer of the flowing fluid and the acoustic energy is directedopposite to the direction of flow. The acoustic energy can be focusedand the fluid can be flowing in a tube.

The transducing means can comprise an ultrasound head comprising one ormore ultrasound transducers. In some embodiments the number ofultrasound transducers is at least three and two of the transducers areused to detect the presence of acoustically active particles and toinfluence the operation of the remainder of the transducers. In apreferred embodiment, the transducing means are comprised of a discshaped main transducer surrounded by an outer ring shaped transducer,the outer transducer being driven in an anti-phase manner to the maintransducer. The acoustic energy can be either focused or not focused.

One embodiment of the system of the invention comprises means forproviding ultrasonic energy for selectively stopping, breaking apart,shrinking, and dissolving acoustically active particles immersed inblood flowing in the carotid arteries. This system can further comprisea disposable pillow, two ultrasonic heads one located on each carotidartery, and two ultrasonic heads each comprising at least two ultrasonicbubble detectors for detect acoustically active particles and/or fluidflow and at least one ultrasonic transducer to provide the ultrasonicenergy.

The surface in the system can be a membrane or have a honeycombstructure to aid in breaking apart and/or holding the acousticallyactive particles. The membrane acting together with the acoustic energyacts as a semi-permeable membrane, which acts to remove acousticallyactive particles from the flowing fluid in which they are immersed.

In a preferred embodiment of the system of the invention, the vesselthrough which the fluid flows is an arterial line of a cardiopulmonarymachine, contrast media catheter, or a dialysis machine or a high-flowvenous line.

In a preferred embodiment of the system of the invention, theacoustically active particles comprise encapsulated material. Theacoustically active particles are delivered to a selected location in avessel by the flowing fluid, concentrated at the location within thevessel and the encapsulated material is released at the location byshrinking and/or breaking apart and/or dissolving the particles. Theacoustically active particles can be introduced into the flowing fluidby use of a specially designed balloon catheter. The encapsulatedmaterial can be a drug and the vessel can be part of the vascular systemof a human or animal body.

All the above and other characteristics and advantages of the inventionwill be further understood through the following illustrative andnon-limitative description of preferred embodiments thereof, withreference to the appended drawings.

BRIEF DESCRIPTION OF THE DRAWING

FIG. 1A schematically shows the velocity profile of a fluid flowing in acylindrical tube;

FIG. 1B schematically shows the velocity curve of a fluid flowing in thevicinity of an arbitrarily shaped surface;

FIG. 9A schematically shows the arrangement of ultrasound radiation,surface, and particle immersed in a fluid that is called for to carryout the method of the invention;

FIG. 2B schematically shows the forces on the particle and the path ofits motion as a result of those forces;

FIGS. 3A to 3C schematically show the breaking up of a bubble by abruptpressure changes;

FIGS. 4A and 4B are photographs showing the before and after state(respectively) of an air bubble held against a bottle wall which wasstruck hit several times by a plastic pen;

FIG. 5 shows schematically the principle waveform;

FIG. 6 show schematically a preferred embodiment of the ultrasonic headof an apparatus for stopping and dissolving air bubbles in the commoncarotid arteries;

FIG. 7 is a diagram showing one embodiment of the communicationconnections between the three transducers of the ultrasound head shownin FIG. 6;

FIG. 8 schematically shows the effect of the ultrasound fields producedby the transducers of the ultrasonic head shown in FIG. 6;

FIGS. 9A and 9B show schematic cross-sectional and perspective viewsrespectively of a preferred embodiment of the device of the invention;

FIG. 10 schematically shows a preferred embodiment of the invention usedas an in-line device;

FIG. 11 schematically shows the apparatus used for selectively slowingdown, stopping, arresting, accumulating, dissolving the shell, andreleasing the material encapsulated within acoustically active particlesimmersed in a flowing fluid;

FIGS. 12A to 12H schematically show another preferred embodiment of theinvention, which comprises a membrane to aid in breaking up and/orholding the bubbles;

FIG. 13 schematically show the ultrasonic wave form used to causebubbles to oscillate;

FIG. 14 is a graph showing a simulation of the spectral decomposition ofa single ultrasonic pulse;

FIG. 15 schematically shows a preferred embodiment of an in-line device;

FIGS. 16A and 16B schematically show how the “Doppler” transducers areused to align the ultrasound head shown in FIG. 6 with the fluid flowdirection;

FIGS. 17A to 17C show a non-limiting preferred embodiment of thecatheter used to introduce the drugs into the bloodstream; and

FIGS. 18A and 18B schematically show respectively an intensity graph anda simple scheme of the transducer head embodiments of an ultrasonic headthat produces a field that confines acoustically active particles to theregion of highest ultrasonic pressure.

DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS

In this application the following terms are used in the followingfashion:

-   -   The terms “ultrasound”, “ultrasound field”, “ultrasound field of        waves”, “ultrasound waves”, “ultrasonic field”, “ultrasonic        field of waves”, “ultrasonic waves”, etc. are used        interchangeably.    -   The term “acoustic radiation force” refers to the force exerted        on acoustically active particles immersed in a fluid when        exposed to a field of ultrasound waves.    -   The terms “bubble”, “acoustically active particle”, and        “particle” are used in a generic sense to include bubbles of all        sizes from “microbubbles” (diameters on the order of        micrometers) to “macrobubbles” (visible to the unaided eye).        These terms also are used to mean “droplet” or “drop”, which, as        far as the present invention are concerned, are equivalent to        bubble and also such terms as “microspheres”, fluids immersed in        other fluids, etc. In general, the term “acoustically active        particle” applies to all cases in which one or more fluids are        immersed in another fluid that is in a more dispersed phase.        Irregardless of whether the dispersed phase is a liquid or a        gas, the “acoustically active particle” is the fluid that is        immersed in it. The term “bubble” generally refers to an        immersed gas, but it can also be relevant when describing a        fluid immersed in another fluid. All of these terms can be used        interchangeably herein, unless the context prevents this.    -   The terms “break apart”, “split”, and “shatter”, and similar        terms are used interchangeably to refer to the breaking up of a        bubble into two or more smaller ones. The term “dissolve” is        used to refer to the total break apart of a bubble into        individual molecules and their dispersion in the surrounding        fluid. The term “shrinking” refers to reducing the size of a        bubble according to the method of the invention. The term        “neutralize” which refers to shrinking and/or breaking and/or        dissolving a bubble till the stage that it is either dissolved        or small enough not to interfere with the function of the fluid.    -   The term “arrest” is used interchangeably with the term “stop”        herein, but it further means holding the object in place at the        location at which the object's motion was stopped.    -   Although the fluid is generally referred to herein as “flowing”,        it should be understood that the method of the invention can        also be used in a static situation, which can be considered to        be a special case in which the flow velocity is zero.    -   The term “transducer” (e.g. piezo-electric element,        piezo-ceramics element) is to be understood to also refer to        transducer arrays compromised of several transducers, each of        which can be excited with a different waveform generator.    -   The term “pulsating” is used to describe both full on-off        modulation of the transducer amplitude and partial modulation,        in which case the carrier frequency is modulated with a lower        modulating frequency.    -   The term “membrane” is used to refer to types of surfaces which        can be described as “meshes”, “cells”, “netlike”, etc, and all        terms are used interchangeably.

As will be described in full hereinbelow, the method of the inventionconsists of a number of steps which for purposes of convenience in thedescription of the method and the theoretical background can be dividedinto two groups, which roughly define two stages in the method. In thefirst stage acoustic radiation force is applied to slow, stop, andarrest acoustically active particles immersed in a flowing fluid. In thesecond stage the arrested particles are shrunken or neutralized byeither the same acoustic radiation force or one with a differentstrength or temporal waveform. This division into stages is artificialonly and the two stages can be incorporated into a single process and beapplied simultaneously.

In order to describe, in a clear and relatively simple way, the methodof the present invention for using ultrasonic energy to slow and/orarrest and/or dissolve acoustically active particles, a typicalrepresentative situation will now be described. The situation describedis that in which a bubble immersed in a fluid that is flowing through astraight round tube enters a region in which ultrasonic waves arepropagated in a direction perpendicular to that of the flow direction.The bubble will be pushed by the ultrasonic field in the direction ofthe wall and will slow down until its motion is stopped and it is heldin place against the tube wall. The following theoretical explanationtogether with the specific examples described hereinbelow will allowskilled persons to intuitively apply the principles of the invention toany situation involving the need to remove acoustically active particlesfrom a flowing fluid in which they are immersed. Using the principlesdescribed herein, skilled persons will be able to determine the value ofthe different parameters involved, in order to achieve optimal resultsfor any given situation. Such a determination will require no more thanunderstanding of the method of the invention and a reasonable amount oftrial and error.

The method of the invention is based on the proper application ofseveral known phenomenon. Firstly it is known that the velocity profileof fluid flowing in a vessel under non-turbulent flow conditions has aparabolic shape. The magnitude of the velocity has its maximum value atthe center of the vessel and gradually approaches zero at the vesselwall. This shape velocity profile occurs because of the presence ofincreased frictional forces near the wall surface. In FIG. 1A isschematically shown the velocity profile for a fluid flowing in acylindrical tube. The curve represents the magnitude of the flowvelocity V a distance X from the wall of a cylindrical tube havingradius R.

This parabolic shaped velocity profile is true for a fluid flowing inthe vicinity of any arbitrarily shaped surface, not necessarily the wallof the vessel, which is in contact with the flowing fluid. The surfacecan either be stationary with respect to the walls of the vessel ormoving at a velocity slower than the flow rate of the fluid. In FIG. 1Bis schematically shown the velocity curve for a fluid flowing in thevicinity of an arbitrarily shaped surface. In this figure, V representsthe magnitude of the velocity of the fluid relative to that of thesurface and X the distance from the surface.

The essence of FIGS. 1A and 1B is that the velocity of a flowing fluidrelative to a surface in contact with it gradually decreasing in valueas the distance from to the surface is decreased until it reaches zeroat the fluid-surface interface.

A second known phenomenon is connected to the motion imparted toacoustically active particles in an ultrasonic field. Acousticallyactive particles immersed in a fluid that are exposed to ultrasonicwaves traveling through the fluid will be pushed in the direction of theultrasonic field propagation. Because acoustically active particles aresubstantially different acoustically from their fluid environment, theyare most affected by the ultrasonic energy, and selectively pushed bythe ultrasonic force while the pushing effect on the rest of the fluiddue to the ultrasonic field is negligible. In the case of a flowingfluid, if a component of the ultrasonic field is propagated in adirection essentially perpendicular to the direction of flow, then theacoustic radiation force exerted on the acoustically active particleswhen they enter the ultrasonic field will push the particles towards thewall of the vessel through which the fluid flows, or towards a surfaceplaced in the path of the ultrasonic waves, and will eventually push theparticles against the surface. At the surface the speed of the fluid iszero and therefore the particles, which are assumed to be carried alongpassively in the fluid, will come to rest.

The final phenomenon on which this stage of the method of the inventionis based is that the magnitude of the frictional force between twoobjects (in the present case: particles, surfaces, particles andsurfaces, etc.) is directly related to the magnitude of the force (i.e.the acoustic radiation force) pushing the objects against each other.

The first part of the process of the invention, i.e. selectively slowingthe motion of acoustically active particles immersed in a fluid,eventually stopping their motion, and holding them in place by pushingthem against a surface, is carried out by the following steps:

-   -   (a) exposing acoustically active particles suspended in a fluid        (the fluid flow speed can be zero or greater in any direction)        to ultrasonic field of waves traveling in the fluid medium;    -   (b) aiming the ultrasonic waves towards the surface of a wall of        the vessel containing the fluid or another surface placed in        their path;    -   (c) pushing the particles in the direction of the ultrasonic        field by means of the acoustic radiation force;    -   (d) reducing the speed of the acoustically active particles,        which is equal to that of the fluid surrounding them (assuming        no self-propulsion of the particles) as they are progressively        pushed into regions of the fluid closer to the surface, or by        the application of an appropriately directed acoustic radiation        force;    -   (e) pushing the acoustically active particles against the        surface by means of the acoustic radiation force, thus creating        forces between the surface and the acoustically active particles        which prevent their movement.

Microbubbles are an example of a type of very acoustically activeparticles. At ultrasound frequencies near the resonance frequency of thebubble, the scattering cross-sectional area increases by several ordersof magnitude above the geometric cross section. The larger thescattering cross-section, the more acoustic radiation force will beexerted on the bubble. It is to be noted that only traveling wavesproduce the needed acoustic force to push suspended particles andbubbles. Standing waves would only cause the particles to collect at theacoustic pressure nodes or maxima.

In the simplest arrangements, a single-element ultrasound transducer maybe used to produce ultrasound (i.e. ultrasonic energy). The strength ofthe acoustic force on an object depends on the ultrasound direction,frequency and signal strength, and the size, mass and acoustic qualitiesof the object being acted upon.

Objects that are acoustically different from the surrounding medium areaffected differently by the ultrasonic energy. For example, in anartery, spherical air-filled microbubbles have radically differentacoustic properties and have much lower mass than biconcave fluid-filled(nonresonant) red blood cells or other irregularly shaped fluid-filledcellular blood elements, therefore the bubbles are preferentiallyaffected by the acoustic radiation force. For an in-depth understandingof the affect of ultrasound on tissues and bubbles the book “UltrasoundIn Medicine” edited by F. A Duck, A. C. Baker, H. C. Starritt, Instituteof Physics Publishing, of the institute of Physics, London, 1998. seeespecially Part 4 “Ultrasound and Bubbles” should be consulted.

FIG. 2A schematically shows the arrangement of ultrasound radiation,surface, and particle immersed in a fluid that is required in order tocarry out the method of the invention. An acoustically active particle 1(in this case spherically shaped) is suspended in a fluid. Vz is thevelocity vector of the fluid and suspended bubble (in the absence of theultrasonic field). The horizontal line represents a surface 4, e.g. awall of the vessel containing the fluid. An ultrasound transducer 2generates acoustic radiation pressure waves 3 in a direction indicatedby arrow 5.

In the example shown in FIG. 2A, the ultrasonic radiation force appliedto the particle is F and the mass of the particle is m. As a consequenceof the viscosity, a frictional force F_(vis) is also exerted on theparticle in the direction opposite to that of F.

F_(vis) is determined from the following equation:F _(vis)=6πrνη  (1)Where:

-   -   r=the particle radius;    -   μ=the particle velocity    -   η=viscosity coefficient

The equation of motion is: $\begin{matrix}{{m\frac{\mathbb{d}v}{\mathbb{d}t}} = {{F - F_{vis}} = {F - {KV}}}} & (2)\end{matrix}$

Where: K=6πrη

In case the particle is a bubble p is the gas density (for air≈1 Kg/m³).$\begin{matrix}{m = {{\rho \cdot \frac{4\pi}{3}}r^{3}}} & (3)\end{matrix}$

The solution of equation (2) is: $\begin{matrix}{{V(t)} = {{{\frac{F}{K}\left\lbrack {1 - {\mathbb{e}}^{\frac{t}{\tau}}} \right\rbrack}\quad{where}\text{:}\quad\tau} = \frac{m}{K}}} & (4) \\{{{Therefore}\text{:}\quad\tau} = {\frac{m}{K} = {\frac{{\rho \cdot \frac{4}{3}}\pi\quad r^{3}}{6\pi\quad r\quad\eta} = {\frac{2}{9}\rho\quad\frac{r^{2}}{\eta}}}}} & (5)\end{matrix}$

If the particle is in the order of microns (e.g. a microbubble) it canbe assumed that the bubble reaches its limiting speed in a negligibletime (for example around 40 μsec for a 20 μm diameter air bubble)thereby simplifying the equation.

Therefore: $\begin{matrix}{V = \frac{F}{K}} & (6)\end{matrix}$

The acoustic radiation pressure (P_(rad)[N/m²]) is calculated from theultrasonic power per surface unit of area (W_(area)[W/cm²]), divided bythe speed of sound in the medium (c[cm/s]). If the application of theacoustic pressure is applied to biological systems, than taking intoaccount the very effective heat perfusion to a rapidly streaming blood,radiation power/output of 100-200 W/cm² can be applied for a knownperiod of time which allows for transfer and spread of the heat to thesurroundings as the fluid (blood) advances in the body's vascularnetwork without causing excessive heating (similar to a radiatoreffect). The period of time depends on, among other factors, the fluidvolume and flow rate and can be determined by applying the Dewy andSparto “thermal dose equation” [S. Separeto and W. Dewey, “Thermal dosedetermination in cancer therapy,” Int. J. Radiat. Oncol. Biol. Phys.,vol. 10, pp. 787:800, 1984.] and the Pennes “bio-heat transfer equation”[H. H. Pennes, Analysis of tissue and arterial blood temperatures in theresting human forearm,” J. Appl. Phys., vol. 1, pp. 93:122, 1948].

The force upon the particle will be the radiation pressure (P_(rad))multiplied by the geometric cross section (the surface facing thedirection of propagation of the radiation).

In the case of a spherical particle (e.g. microbubble) the acousticforce will be:F _(rad) =P _(rad) ·πr ²  (7)

The limiting speed of the particle in the direction of the surface is:$\begin{matrix}{V = {\frac{F}{K} = {\frac{{P_{rad} \cdot \pi}\quad r^{2}}{6\pi\quad r\quad\eta} = \frac{P_{rad} \cdot r}{6\eta}}}} & (8)\end{matrix}$

Therefore the time it takes for the particle to travel a distance R toreach the surface is: $\begin{matrix}{t = \frac{6{R \cdot \eta}}{P_{rad} \cdot r}} & (9)\end{matrix}$

If for simplicity (as in this illustrative example), the particle isimmersed in a fluid medium which moves in a direction that isperpendicular to both the radiation force and the surface, and thesurface is flat (note that in general neither the radiation force northe surface have to be perpendicular to the fluid flow direction and thesurface does not have to be flat); then the propagation profile of theparticle upstream is described by Bernouli's equation. The velocity ofthe fluid and the particle decelerates as the surface is approached,until complete arrest of the motion particle is achieved as a result ofincreased friction forces.

FIG. 2B schematically shows the forces on the particle and the path ofits motion as a result of those forces. The forces are as described withrespect to FIG. 2A. AZ is the distance, in the z (flow) direction, thatthe bubble moves parallel to the surface, until it reaches the surface.R is the distance of the bubble from the wall before it is acted upon bythe ultrasonic force.

The velocity profile is: $\begin{matrix}{{V_{z}(x)} = {{{V_{z}(o)}\left\lbrack {1 - \left( \frac{x}{R} \right)^{2}} \right\rbrack} = {{V_{z}(o)}\left\lbrack {1 - \frac{V^{2}t^{2}}{R^{2}}} \right\rbrack}}} & (10)\end{matrix}$

While approaching the surface the particle travels upstream a distanceof: $\begin{matrix}{{{\Delta\quad Z} = {{{V_{z}(0)}{\int_{0}^{R/V}{\left( {1 - \left( \frac{Vt}{R} \right)^{2}} \right)\quad{\mathbb{d}t}}}} = {{V_{z}(0)}\left\lbrack {\frac{R}{V} - {\frac{1}{3}\frac{R}{V}}} \right\rbrack}}}{{{therefore}\text{:}\quad\Delta\quad Z} = {\frac{2}{3}{{V_{z}(0)} \cdot \frac{R}{V}}}}} & (11)\end{matrix}$

The properties of the surface (biological, inorganic material, etc.),the particles (gas filled, fluids filled, geometry, etc.), and thesurroundings (biological, heat doses, flow velocity, etc.) have to beconsidered when choosing the properties of the ultrasonic wave to beused.

The second stage of the method of the invention, i.e. the breaking upinto smaller bubbles and/or dissolving of acoustically active bubblesthat are held in place against a surface will now be described.According to the kinetics of the dissolution process for bubbles in aliquid based on Epstein and Plesset equation [Epstein P S, Plesset, M S,“On the Stability of Gas Bubbles in Liquid-Gas Soluions”, J Chem Phys18:1505-1509, 1950.], gas bubbles naturally shrink as a result of thesurrounding pressure. [Alexey Kabalnov, et. al., “Dissolution ofMulticomponent Microbubbles in the Bloodstream”, Ultrasound in Med. &Bio., 1998, 24:739-749]. The estimated for the rate of decrease of theparticle radius over time is: $\begin{matrix}{\frac{\mathbb{d}r}{\mathbb{d}t} = {{- {DL}}\quad\frac{{\overset{\_}{p}}^{*} + {2{\sigma/r}}}{p_{atm} + {4{\sigma/3}r}}\left\{ {\frac{1}{r} + \frac{1}{\sqrt{\pi\quad{Dt}}}} \right\}}} & (12)\end{matrix}$where D is the diffusivity of air in water, L is the partitioncoefficient of air between water and gas phase, P_(atm) is theatmospheric pressure, {overscore (p)}* is the excess pressure, which hasa contribution from both the systemic blood pressure and the oxygenmetabolism. σ is the surface tension, r is the radius of the bubble, andt is time. The smaller the diameter the faster the bubbles dissolve intothe medium. For example, bubbles of around 10001 μm take more than 2months to dissolve in saturated fluid, 100 μm bubbles take around 10minutes to dissolve, and a 10 μm bubble dissolves in around 6 sec underthe same conditions. Therefore by breaking the bubbles into smallerbubbles a more efficient dissolving process is produced.

One of the mechanisms for breaking up the bubbles is to increase theefficiency of the diffusion process is based on the observation that, ifforces due to abrupt pressure changes are exerted on the surface of abubble, then it will deform and split (break) into smaller bubbles.

The breaking up of a bubble by abrupt pressure changes is schematicallyshown in FIGS. 3A to 3C. In FIG. 3A is shown a gas macrobubble 1 trappedagainst the flexible wall of a bottle 6. A fingertip 7 is advancing inthe direction shown by arrow 8 towards the bottle wall and the bubble.In FIG. 3B is shown the instant that the fingertip hits the bottle walland FIG. 3C an instant later when the finger is pulled back. The“whiplash” strike exerts shearing forces on the bubble, breaking it to agroup 9 of smaller bubbles. The process can be repeated until the sizeof the bubbles is reduced to a critical value at which point theydissolve completely in the surrounding fluid.

This phenomenon can be easily demonstrated by holding a macrobubbleagainst the flexible wall of, for example, a standard, 1.5 liter bottlecontaining water. FIGS. 4A and 4B are photographs showing the before andafter state (respectively) of an air bubble held against a bottle wallwhich was struck several times by a plastic pen.

FIG. 14 is a graph showing a simulation of the spectral decomposition ofa 1/T sec⁻¹ long ultrasonic pulse. It can be seen that in thedelta-function of a single pulse, most of the energy is concentrated atlower frequencies. By narrowing the pulse more energy is transferred tohigher frequencies, but still most of the energy remains at the lowfrequencies. When generating a Chirp function comprising of multiplemodulation frequencies around the correct bubble breakup frequency,close to a bubble's natural deformation resonance, more energy istransferred to the selected frequency, which in turn escalates thebubble oscillations, with the use of less energy and therefore lessheat. Alternatively, if the resonance frequency is known only the exactmodulation frequency is applied.

The principles described hereinabove are applied, according to themethod of the invention, by using ultrasonic energy on gas bubblesimmersed in a fluid in a vessel to shrink the gas bubbles and eventuallyto dissolve them. The process is carried out by different mechanismswhich are related to the manner in which the acoustic radiation force isapplied to the bubble.

Two techniques that are used to cause stimulated shrinking of gasbubbles according to the method of the invention are based on applyingthe acoustic radiation force having a temporal waveform to the bubble.The temporal waveform causes shrinking of the ultrasonically activeparticles faster and more effectively then use of a continuous wave. Theultrasonic waveform can be generated by the same ultrasonic transducerused for moving the bubbles to the wall of the vessel, or by a separateacoustic source.

The first shrinking technique relies on application of a pulsating fieldto alternately compress and release the bubble therefore increasing theefficiency of the diffusion process. The theoretical principles on whichthis technique is based are discussed in the article entitled“Enhancement of Sonodynamic Tissue Damage Production by Second-Harmonicsuperimposition: Theoretical Analysis of Its Mechanism” (S. I Umemura,K. I Kawabata, and K. Sasaki, IEEE Transactions on ultrasonics,ferroelectrics and frequency control, vol. 43, no. 6, 1996) in which itis shown that expanding gas bubbles by rectified diffusion usingrelatively low harmonic ultrasound frequencies (about 0.5 MHz and 1 MHz)and inducing asymmetric oscillation of bubble pressure with relativelysharp valleys and broad peaks, is feasible.

In the present invention relatively high harmonic ultrasound frequencies(for example about 5 Mhz to 10 Mhz) are employed and asymmetricoscillation of bubble pressure is induced with relatively sharp peaksand broad valleys to achieve the opposite effect to that achieved byUmemura, et. al. This waveform is applied in order to accomplish optimalbubble compression and diffusion of the gas from inside the bubble tothe surrounding medium safely and without causing cavitations and jetformation that can be harmful to the surface against which the bubble isheld. In FIG. 5 is shown schematically the principle waveform. Thepattern of acoustic waves (waveform) can be applied during all or partof the described process, i.e. at any time from the beginning of thepushing until the bubble is finally dissolved. Even if negativerectified diffusion of gas inside the bubble to the surrounding mediumis not achievable, reducing the rectified diffusion to zero or close tozero allows the use of higher wave field intensities and thereforegreater radiation force for the same mechanical index as that of a puresine wave, therefore reducing the probability of cavitations and jetstream formation. This is most important in clinical settings whereregulatory agencies limit the Mechanical Index that can be applied toliving tissues and blood components.

The second technique for accelerating the process of dissolving the gasbubbles is the use of ultrasonic pressure, preferably with theassistance of the surface or wall, in order to cause shape deformationand break apart of a large bubble into a number of smaller bubbles whichwill dissolve more rapidly into the surrounding fluid. By causing thebubble to oscillate at its natural oscillation frequency a relativelyweak pulsating (or modulated) pressure can cause the bubble to breakapart.

According to the Hinze equation: $\begin{matrix}{N = \frac{Td}{\sigma}} & (13)\end{matrix}$

[Hinze. J. O. “Fundamentals of the Hydrodynamic Mechanism of Splittingin Dispersion Processes.” AlChE J. 1, 289-295, 1995] it can be shownthat, if T is the stress caused by the ultrasonic pressure, d is thebubble diameter, and σ is the bubble surface tension, the equationresults in the value of the dimensionless quantity N. For certain typesof drops and bubbles N is related to the Weber number, which helps todefine and characterize the breakup mechanism of the bubble. The largerthe Weber number, the more significant is the breakup effect. Thesmaller the diameters of the bubbles, the greater the acoustic forcethat must be applied in order to achieve breakup Weber numbers. Theprobability of breaking bubbles having subcritical Weber numbers can beincreased by generating the optimal forcing frequency for the bubble,which is the natural oscillation frequency of the bubble. For the simplecase of spherical bubble, the natural oscillation frequency is:$\begin{matrix}{\omega_{n} = {{2\pi\quad f} = \sqrt{\frac{\left( {n - 1} \right)\left( {n + 1} \right)\left( {n + 2} \right)}{\rho_{c}}\frac{\sigma}{a^{3}}}}} & (14)\end{matrix}$

Where σ is the surface tension, ρ_(c) the surrounding medium pressure,for spherical mode n=2 and a is the bubble diameter. The smaller thebubble, the higher its oscillation frequency. See article by [F. Risso“The Mechanisms of Deformation and Breakup of Drops and Bubbles” Multi.Sci. Tech. Vol. 12, pp. 1-50, 2000]

As the bubbles are pressed against the surface by the ultrasonic field,asymmetric pressure surrounds the bubbles (on the sides of the bubble incontact with the surface and the fluid). This enhances the oscillationsof the bubbles, which result in fragmentation of the larger bubbles intosmaller ones. As discussed hereinabove, the smaller the bubble thefaster it shrinks diffuses to the surrounding medium. In contrast to thecavitational effect where the oscillations are associated with volumeoscillations, oscillations induced by this technique are isovolumic,therefore deformation induced by this technique are nonviolent andsubtle. These oscillations do not cause excessive shearing pressure onthe surface violent bubble collapse, and jet formation generallyassociated with volume cavitations (as appose to shape deformationwithout changing the bubble volume).

An example of the ultrasonic wave form used to cause the bubbles tooscillate is schematically shown in FIG. 13, which is not drawn toscale. The carrier frequency is either modulated fully (on-off) oramplitude modulated (AM) with modulated frequency which is sweptrepetitively from a low frequency to a high frequency, and again fromlow to high and/or from high to low through several or all frequenciesin the range in a short time period. As a specific, nonlimitativeexample, the carrier frequency 100 can be 2.2 MHz and the modulationfrequency is swept from 10 KHz to 70 KHz in three steps 101, 102, 103.

The ultrasonic field/s generated by the acoustic source or sources, canbe focused to a specific volume or point in the medium in order toincrease the acoustic radiation forces at that location.

The ultrasonic field/s can be applied in a continuous state, or can begenerated on command by a human operator or automatically by use of anelectronic device. The ultrasonic field can be generated after detectionof the acoustically active particles by a special ultrasound transducerthat uses the Doppler principle or any other detection method known toskilled persons.

Skilled persons will know how to determine the optimal values of theultrasonic field intensities, duty cycles, frequencies, and the numberof acoustic sources, their shapes, dimensions, placement and acousticproperties, for a given application and set of environmental parameters,by applying the principles discussed herein.

Except for cases where it is necessary to use low intensity and lowfrequencies, ultrasonic waves at frequencies much greater than theresonant frequencies of the acoustic active particles can be used in themethod of the invention. In general the ultrasonic frequencies used areabout 1 MHz and higher, preferably between 2 MHz and 10 MHz. In theparticular case of air microbubbles, frequencies in the range of about 1MHz and higher can be used. These frequencies are chosen to avoidcavitations and jet formation that could damage the fluid or surface.

The methods discussed hereinabove for selectively stopping anddissolving gas in moving fluids will now be applied to the design ofseveral devices in order to illustrate how the invention can be appliedin specific situations. The embodiments of the device of the inventiondescribed herein below are meant to be illustrative only and notlimitative. Although the examples chosen are from the field of medicine,it is again stressed that the method of the invention will be useful inmany industrial situations from many different fields.

The sources of the ultrasonic energy (transducers) have to be able tocreate fields with different magnitudes and wave forms and be able toperform different functions such as detection, determination of particlesize, pushing, arresting, and breaking up the bubbles in the differentembodiments of the invention described herein. Before describingspecific embodiments, some general methods of operation of thetransducers will be described in order to give the skilled person enoughinformation to adopt the method of the invention to any possiblesituation.

-   1. A method that does not detect the bubbles or measure their sizes    (“shooting blind”): A single generator generates a pulsating carrier    (main frequency) in a chirp mode as shown in FIG. 13. The waveform    shown translates into a modulated ultrasonic radiation field. When    different sized bubbles pass through it at the same time, each will    oscillate and break apart when the correct pulsating and/or    modulated force is exerted upon it. A large bubble passes through    several pulse cycles (or regimes) until it breaks into increasingly    smaller bubbles. The pulsating ultrasonic force will also push the    bubbles towards the vessel wall or surface causing them to be    arrested against the surface. In the case of a net or honeycomb cell    at or before the surface, as will be explained hereinbelow, the    large bubble will break, on impact, into smaller bubbles that are    arrested behind the net or inside the cells).-   2. Another “blind” method: The generator is caused to pulsate or is    modulated at the chirp modulation frequencies given with reference    to FIG. 13, while always maintaining a low intensity CW (continues    wave) signal in order to arrest the bubble already stuck at the    friction layer, further preventing them from moving.-   3. Using one or more transducer and generators which deliver    different carriers simultaneously, by chirping all the carriers with    different modulation frequencies, several different bubble sizes can    be handled and broken up at once.-   4. Using an ultrasound, electro-optic, or other type of detector, in    order to detect incoming bubbles and activating the breaking    transducer only when there are bubbles present and/or automatically    adjusting the modulation frequency to the bubble size and shape.    Another detector can be used downstream to assure that no bubbles    have passed the bubble breaking/dissolving transducer.

All the above methods can comprise the superimposition of two or morefrequencies in order to further shrink the bubbles, or allow higherultrasound intensities without causing cavitations.

The purpose of the preferred embodiment of the device of the inventionschematically shown in FIGS. 6 to 9B is to stop and dissolve air bubblesin the common carotid arteries. In FIG. 6 is schematically shown apreferred embodiment of the ultrasonic head of the device.

The ultrasound head 20 comprises of two “Doppler” elements 21 and 23 themain ultrasound transducer 22 and expansion slots to allow theattachment of additional transducers 24 if desired in order to give thedevice better arrest and dissolve capabilities. The length of the headis about 5 cm or shorter, to fit the length of the common carotid arteryof an average human. A pediatric version of the invention should beshorter.

The first “Doppler” element 21 of head 20 is an acoustic source (e.g.,piezo-electric transducer) capable of detecting blood flow in thecarotid artery by analysis of the Doppler effect and distinguishingbetween blood free of acoustically active particles and the presence ofbubbles in the blood. Suitable acoustic sources with the requiredcapabilities are common in the art and are commercially available.

The second transducer (or transducers) 22 is the acoustic sourcedescribed hereinabove for carrying out the method of the invention, i.e.safely and selectively stopping, breaking apart, and shrinking thebubble. In this case the surface against which the bubbles are arrestedis the arterial wall and the pushing and shrinking process isaccomplished by modulating the frequency to the optimal breakingfrequency, and breaking the bubbles into smaller bubbles that dissolvemore rapidly. This process can also be accompanied by the use ofsuperimposed waveform as shown in FIG. 5 to allow the use of higherultrasonic fields while still avoiding the rectified diffusion processthat might cause cavitations. In cases where there is no danger ofdamage to the vessel wall, the bubbles can be made to hit the vesselwall with sufficient momentum to split them into smaller bubbles uponimpact. In either case, after the bubbles reach the wall the acousticelement keeps pulsating, in order to break the bubbles held against thevessel wall into smaller and smaller bubbles as described hereinabove.

The third transducer 23 has the same acoustic properties as the firstone. It detects blood flow, and air bubbles (acoustically activeparticles) in the blood. If bubbles manage to pass the secondtransducer, the third one detects them and alerts the user, and/orchanges the second transducer's acoustic output via a feedback mechanismin order to improve the efficiency of the process.

Air bubbles, suspended in the bloodstream passing through the carotids,are detected by the first transducer and selectively and safelyneutralized (stopped, broken up into smaller bubbles, and shrunk by useof a special waveform designed for this purpose) by the secondtransducer. The third transducer provides confirmation that the bubblesdetected by the first one have been neutralized by the second andprovides feedback to the second transducer if necessary.

FIGS. 16A and 16B schematically show how the “Doppler” transducers areused to align the ultrasound head shown in FIG. 6 with the fluid flowdirection 26, in cases where the vessel 25 through which the fluid flowsis hidden from view. The first 21 and third 23 transducers in theultrasonic head locate the vessel 25 by sensing the fluid flow throughit. By comparing intensities of the signals detected by bothtransducers, the alignment of the long axis of the ultrasonic head withthe fluid flow direction can be achieved.

In this preferred embodiment, the inputs of the first and thirdtransducers are connected to the second transducer's output, in order toapply a suitable ultrasound output for pushing the bubbles to the wallwithin the ultrasound waves field; and, at the same time, to apply theexact waveform required for shrinking the bubbles, according to theparameters of the bloodstream, diameter of the bubbles, bubble volume,etc.

FIG. 7 is a diagram showing a preferred embodiment of the communicationconnections between the three transducers of the ultrasound head of thepreferred embodiment described above. The electronic components 40 areactivated by computer (or a microcontroller, chip, etc.) 46 which iscontrolled by appropriate software or embedded in the hardware. In thefigure, tube 44 represents the carotid artery and arrow 45 the directionof blood flow. The first, second and third transducers are respectivelydesignated by numerals 21, 22, and 23. The rest of the components shownare: duty cycle establisher multivibrator circuits 47, amplifiers 48,voltage controlled amplifier 49, waveform generators 50,oscilloscopes/FFTs (Fast Fourier Transform) 51, and switches 52.

FIG. 8 schematically shows the effect of the ultrasound fields producedby the transducers of the ultrasonic head described hereinabove onacoustically active particles 1 (e.g. gas bubbles or liquid drops)immersed in a fluid flowing in a vessel 60 (e.g. a plastic tube or pipeor a carotid artery). The black arrows 62 indicate the velocity vectorsof the fluid flowing in the vessel (faster flow speed towards themiddle). Bubbles 1 traveling through the vessel in the general directionindicated by white arrow 63 are detected by a “Doppler” acoustic source21 capable of detecting acoustically active particles in a medium bysending, receiving, and analyzing ultrasound energy 64. The source 21 isalso capable of detecting flowing fluid, like blood flowing in thecarotid. After the bubbles have been detected by the “Doppler” source,the main acoustic source 22 is activated creating acoustic radiationpressure waves 3. The ultrasound waves propagate in the generaldirection of the white arrow 5 and the black arches 61 indicate theboundaries of the ultrasonic field generated by transducer 22. The focuscan include the vessel and the surrounding, all of the vessel or part ofit. The focus site (point or volume) is not limited to a specific shapeor size, and is determined by the properties of the acoustic source (orsources) in order to achieve the best stopping and dissolvingcapabilities for a given set of conditions As the bubbles enter theultrasonic field, acoustic force is exerted on them in the direction ofthe field 5, pushing them towards the vessel's wall. At the same time,they are advancing with the flowing fluid. The direction of their motionis shown by arrow 63′. As they approach the wall they are slowed downbecause of increased friction between the fluid and the wall, until theyeventually stop moving and are held against the wall. This situation isindicated in the figure by numeral 65. The bubbles are next broken intosmaller faster diffusing bubbles as explained above. Another “Doppler”source 23 monitors the vessel for any remaining bubbles and provides afeedback loop for the system. The feedback loop can be used to changethe parameters of the main acoustic source 22 in order to achieve betterarrest and shrinking capabilities.

When a bubble is placed in an ultrasonic field, the radiation forcepushes it forward. It will however, also move side ways toward areaswhere the force is minimal. If however, the radiation field is as isshown in FIG. 18A., (where the X axis represents the distance from thetransducer's central axis and the Y axis represents the pressureintensity) and the bubble is initially at the center of the field (theinner field), it will move forward only. Such a field is easily producedby a transducer, which is for exampled comprised of a circulartransducer to which an outer ring has been added, as in FIG. 18B. Theouter ring-shaped transducer 201 is driven in anti-phase to the maindisc-shaped transducer 202. When a bubble is trapped inside the innerfield 203, it can not escape because the higher pressure at theperimeter diverts it back towards the center.

The method of stopping the bubble by pushing it to the vessel wall orsurface and breaking the bubble into smaller bubbles by applying apulsating frequency can now be carried out as described herein. Theshape of the head is not limited to circular and can be, for exampleelliptical or rectangular. The ultrasonic head can be focused at anydistance or not focused and the field produced can be used to trap asingle bubble or a group of bubbles at the same time.

FIGS. 9A and 9B show schematic cross-sectional and perspective viewsrespectively of a preferred embodiment of the device of the invention.The device 70 comprises two ultrasonic heads 20 one for each of the twocarotid arteries 44, one of which is located on each side of the neck.The dashed lines 74 in FIG. 9A schematically represent the boundary ofthe ultrasonic field inside the neck The ultrasonic heads 20 aresituated on adjustable supports 71 which allow freedom of movement ofthe ultrasonic heads in all directions to permit easy adjustment andprecise alignment of the heads with the arteries. The patient's neck isplaced on a specially designed inflatable head and neck pillow 72 (madefrom foam or sponge, etc.), in order to prevent acute changes of thepositioning of his head and neck. The base of the apparatus 73 cancontain the electronics for the device, or the electronics can be placedin a separate container. Other instruments (monitor, user interface,etc.) should be placed in the most convenient manner. This embodiment ofthe invention is a device that can be used for the supply of blood thatis free from microbubbles and particles from a heart-lung machine or onthe patient's neck during open-heart surgery and other invasiveprocedures to prevent the harmful microemboli from reaching the brain.

Another preferred embodiment of the invention is an in-line device forstopping and dissolving air bubbles embedded in a fluid flowing througha line, i.e. a tube or pipe. Some examples from the field of medicine oflines with which this embodiment can be used are: arterial lines of acardiopulmonary machine, contrast media catheters, dialysis machines,and high-flow venous lines. This embodiment is a simplified version ofthe embodiment described hereinabove. In its basic form, the devicecomprises only one transducer but, in the preferred versions has atransducer array. The “pushing” acoustic element (e.g. piezo-electrictransducer or transducer array) creates an acoustic radiation pressurefield as described hereinabove. The element supplying the acousticenergy is turned on and off in a special cycle regime that is determinedto accomplish the best arresting and dissolving capabilities for aspecific line. The bubbles are pushed towards the vessel wall by thepulsating high frequency ultrasonic energy field, the bubbles may onlybe stopped at the vessel wall or, since there is no danger of damage tothe wall in this case, they can be made to hit the vessel wall withsufficient momentum to split them into smaller bubbles. In either case,after the bubbles reach the wall the acoustic element keeps pulsating,in order to break the bubbles held against the vessel wall into smallerand smaller bubbles as described hereinabove.

FIG. 11 schematically shows a preferred embodiment of the in-line device80 described in the previous paragraph. A piezo-electric transducer 81is attached by being clipped, glued, threaded, or by any other suitablemeans to a hollow tube 82 (the line) containing fluid flowing throughit. For this use, a preferred ultrasonic cycling regime consists of anultrasonic energy pulse for the time it takes a bubble to reach thevessel wall with sufficient momentum to be deformed and to split intosmaller bubbles by the shearing forces on the bubble followed by aboutone cycles of rest. For example, if ultrasonic energy of about 100 W/cm²is applied it takes about 20 msec for a bubble with a radius of 10 μm toreach the wall of a vessel 0.8 cm in diameter; Therefore a cyclic regimecomprised of a 20 msec ultrasound pulse followed by 20 msec of rest canbe used (1:1 ratio). To increase the efficiency, each pulse can befurther modulated at the bubble's deformation frequency. (refer to theequation number 14 above)

Other embodiments of the in-line device can incorporate bubble detectors(ultrasonic, optical etc.), and superimposition mechanisms as describedhereinabove and can be focused and adjusted to best fit a givensituation. In the case of the medical examples mention above, theapparatus prevents dangerous particles and air bubbles from entering thebody's blood circulation system and reaching vital organs in the body,where they can cause ischemia and damage.

FIG. 15 schematically shows a preferred embodiment 110 of the in-linedevice described in the previous paragraphs. In this embodiment thefluid line 114 and the medium surrounding it preferably has an acousticimpedance close to that of the flowing fluid. The line (tube) is bent sothe fluid flows (flow velocity indicated by dark arrows) towards theultrasonic head 113. The ultrasonic head is focused on the axis of thefluid line, where the flow is the fastest. A bubble 111 flows in thefluid (the bubbles tend to flow at the center of the tube) in a regionwhere it is not affected by the ultrasonic field. The field generated ismodulated at the bubbles optimal breakup frequency (by finding thebubble size using a detector, or by generating a predetermined chirpwaveform). The transducer generates a force field which functions as aselective bubble barrier. This barrier can serve two functions: toselect which size bubbles can pass and which cannot and also to isolatethe volume of the fluid in which bubbles are immersed from bubble-freeregions. When the bubble 111 approaches the focal region, it is brokenup into a group of smaller bubbles 112. These bubbles are pushedbackwards, against the flow direction and then advance again, beingbroken down into even smaller bubbles when the reenter the focal region.The larger the bubble the larger the force exerted on it pushing itbackwards. Because the field is focused it tends to spread out after thefocus, sending the bubbles back and toward the wall of the tube. Theintensity of the ultrasonic waves can be determined to allow bubblessmaller than a certain size to pass the “ultrasonic barrier” or not toallow any size of bubble to pass, i.e. to force all bubbles to dissolvecompletely into the fluid. In FIG. 15, numeral 115 represents a supportfor the tube and/or a shield to which absorbs the ultrasonic energyoutside of the tube. Curved lines 116 designate the shape of theultrasonic field.

FIGS. 12A to 12H schematically show another preferred embodiment of theinvention. The membrane (e.g. cells, net, mesh) is a type of surfacewith unique attributes (pores). The membrane acts as a semi-permeablemembrane which, together with the ultrasonic propagating field, furtherenhance the capabilities of the method for arresting, breaking anddissolving acoustically active particles. This embodiment can be usedwith, for example, blood lines of dialysis and heart-lung machines,high-flow infusion lines, different types of infusion pumps and powerinjectors. In this embodiment the surface against which the acousticallyactive particles are stopped has a honeycomb or netlike surface facingthe fluid. Acoustically active particles are accelerated towards themembrane by the ultrasound field in order to achieve one or all of thefollowing effects:

-   -   breaking bubbles larger than the size of the membrane pores with        the bubble fragments then pushed by the ultrasound force through        the membrane;    -   deforming large bubbles and squeezing them through the membrane        pores; and    -   passing bubbles smaller then the membrane's pore size through        the membrane surface or shatter them on the grid lines.

The membrane and the ultrasonic field prevent the reentry of particlesthat have passed through the member from reentering the main fluid flow.In the area between the membrane and the vessel the friction is high andthe flow speed is low, therefore less energy is needed to keep theacoustic active particles in position.

The system of the invention has advantages over the prior art mechanicalfilters for many uses. For example, as mentioned hereinabove, the poresizes of mechanical filters at heart-lung machine arterial lines islimited in size in order not to compromise the blood particles,therefore many bubbles manage to pass the filter and enter the body. Incontrast, the pore size in this preferred embodiment of the invention isnot limited since the ultrasonic waves are differential and selectivelyaffect the acoustically active particles, while the remainder of thefluid remains unaffected.

Referring to FIG. 12A, the particles (bubbles) 124 enter the device 123through the line 121. The fluid flows in the direction indicated by thearrow 122. The bubble initially travels along the axis of the tube untilit enters the ultrasonic field generated by transducer 130 at whichpoint it is pushed by the ultrasonic force in the direction of themembrane 125. It is to be noted that the membrane, as is the case withall of the preferred embodiments of this invention, can be designed andengineered by skilled persons to provide maximum effect at minimum cost.

FIG. 12B shows the breakup of the bubble into a group of smaller bubbles126 as it hits the membrane. Breakup occurs because of the large andabrupt forces exerted on the bubbles as it impacts the grid of themembrane, as explained in further detail hereinabove, most of the energydue to the impact is located at the lower frequencies (see thedelta-function of a single pulse in FIG. 14). As can be extrapolatedfrom the equation 14, the larger the bubble's diameter the lower itsnatural deformation oscillation frequency (and vice versa) and thereforelarge bubbles more easily break into smaller bubbles. After the bubblespass through the membrane the small bubbles may naturally merge again toform larger bubbles 127. In this case both the membrane and theultrasonic field will prevent the bubble from returning to the mainfield. As explained above, the ultrasonic energy exerts greater force onlarger bubbles. Thus, pushing a large bubble to the wall and preventingit from moving can be done with much less ultrasonic power (and heating)using this embodiment than using an embodiment without the membrane. Asin the other embodiments described herein, the ultrasonic field can bemade to pulsate at optimal deformation frequencies to assist in breakingapart the bubbles.

In FIG. 12C, instead of a single membrane, the bubble passes throughseveral membranes having increasingly smaller openings. By timing theultrasound pulses the bubbles strike the membranes and split intosmaller bubbles (which take less time to dissolve in the surroundingmedium), the bubbles which have not dissolved merge again; or, as shownin FIG. 12D, are pushed into small cells 128 where they cannot merge toform a bubble larger than the cell. If the cell size is smaller than thesize of the original bubble then the bubbles in the cells will dissolvemore quickly than the original bubble.

FIG. 12E shows an embodiment where instead of a membrane, cells 129 (ofappropriate shape and dimensions) in a honeycomb pattern (side by side)are used. In cases in which the fluid is blood, the cell walls andmembrane can be coated with heparin or other anticoagulant substance.The anti coagulant substance can also be spread on a sponge likemateriel in the cells or around the membranes. The outer wall of thecell can be covered with an acoustically matching substance (such asgel), for minimal losses during ultrasonic energy transfer.

In FIG. 12F is shown an embodiment in which the membrane 125 is madewith increasingly smaller holes (typically 0.1 μm to 5 cm in clinicalscenarios) with the direction of the flow indicated by the black arrows122. As described above the acoustically active particles is acceleratedtoward the membrane by acoustic force. As discussed above, largeracoustically active particles reach the surface faster than smallerbubbles, and they break and/or deform at the membrane with relativelylarge pores. In case the frictional forces holding the particles is notsufficient and the particles move with the flow direction the membrane,aided by the ultrasonic field, will prevent them from reentering themain flow stream.

In FIGS. 12G and 12H are schematically shown top and side views ofanother preferred embodiment of the invention which utilizes theconcepts described in connection with the embodiments shown in FIGS. 12Ato 12F. In this embodiment the fluid, with the acoustically activeparticles immersed in it, flows (in the direction of arrows 122) througha tube having a spiral shaped section 131, having entrance 132 and exit133, and comprising a membrane 125 disposed throughout the length of thespiral section. Transducer 130 emits ultrasound waves in the direction134 that is orthogonal to the plane of section 131, thus pushing theparticles toward the membrane 125. The highest strength of theultrasonic field is on the central axis of the transducer which isaligned with the center of the spiral section of the tube. As discussedabove the smaller the size of bubble the closer it will get to thecenter before reaching the membrane surface and being neutralized. Asthe bubbles approach the center of the spiral, they are also approachingthe central axis of the transducer and therefore more force is exertedon them. This pushes them with increasing momentum towards the membranethus neutralizing them more effectively.

Another preferred embodiment of the invention is a method of introducingmaterial encapsulated within acoustically active particles into a vesselthrough which a fluid is flowing by immersing the particles in thefluid; concentrating the acoustically active particles at apredetermined location within the vascular network; and releasing theencapsulated material at the location, either before or after passingthrough the vascular membrane into the interstitial fluid, by shrinkingand/or breaking apart and/or dissolving the particles.

As an illustrative but nonlimitative example of this embodiment, adescription of a method and apparatus for slowing, stopping andaccumulating encapsulated drugs at a specific site in the body, forexample at the location of a tumor is presented.

Referring to FIG. 11, acoustic source 97 comprised of a single acousticelement or an array of acoustic elements produces a focused ultrasonicfield comprised of acoustic pressure waves 95 traveling in the directionindicated by arrows 96. The boundaries of the field are indicated bysolid lines 98 and the focus is 94. The acoustic waves are focused(longitudinally and axially) at a designated site (volume) by means wellknown to skilled persons. The effect of the radiation pressure isgreatest in the focal region and decreases in proportion to the distancefrom the focus, the f number (the relationship between the acousticsource diameter and the distance from it to the focus), the ultrasonicwavelength, and the acoustic properties of the medium.

In the focal zone, the blood flows in different directions inside one ormore blood vessels 90, 91, 92 that are not necessarily perpendicular tothe direction of propagation of the ultrasound field 96. As a result,depending on the relative angle between the bloodstream and theultrasonic field propagation, only part of the acoustic radiation forcewill push bubbles immersed in the bloodstream towards the vessel wall,causing them to stop. In the most extreme case, where the blood flowdirection in a vessel in the focal zone is parallel to the direction ofwave propagation, the waves will not push the bubble towards the wallbut will accelerate it away from the source pushing it towards a vesselwall at the first curve.

A catheter is used to release drugs encapsulated in microbubbles 93 intothe artery (or arteries) which bring blood directly to the targetedsite. This method of introducing the microbubbles minimizes one of thebasic problems of conventional systemic drug delivery methods, i.e. thesystemic circulation of the drug until it eventually reaches thetargeted site. The artery chosen for the introduction of themicrobubbles (91 in FIG. 111) is the one that is as close as possible toperpendicular to the ultrasonic field for the reasons discussed above.

FIGS. 17A to 17C show a non-limiting preferred embodiment of thecatheter used to introduce the drugs into the bloodstream. In FIG. 17A,the catheter 151 is shown inserted into the blood vessel 150 usingfluoroscopy guidelines or any other insertion technique known in theart. Vessel 150 has two side-branches 157 and 158 and it is desired tointroduce the encapsulated drug 154 into branch 157, without allowingany of the drug to enter branch 158 or in any part of vessel 150 beyondbranch 157. During insertion of the catheter, the balloon 152 at the tipof the catheter, is deflated allowing free flowing of blood in allbranches of the vessel 150 (blood flow direction is indicated by theblack arrows). In FIG. 17B is shown the injection method. Beforeinjection (in the direction indicated by double arrow 160) of theencapsulated drug 154 is started, either through a hole in the main tubeor a valve 153, the balloon 152 is inflated by gas or a liquid which isdelivered to it through side tube 155 or the main tube 156. The inflatedballoon diverts all of the blood flow to the specified side-branch 157,thus limiting the systemic spread of the drug. In FIG. 17C, is depicteda situation in which the catheter is deployed against the bloodstream.The balloon and valve can be manufactured in any orientation anddistance from each other in order to allow injection of the drug tospecific vessel or vessels, also any number of balloons and valves canbe used.

Once the microbubbles are introduced into the bloodstream and arrive atthe focal zone of the ultrasound field, they are pushed to the wall ofthe artery, slowed down, stopped, and held in place by the force of theultrasonic waves as described hereinabove. For this application theminimal acoustic force necessary to accumulate the microbubbles at thetargeted site is used at first. Because the drug is encapsulated in veryacoustically active microbubbles, by means of ultrasonic imaging, theoperator (the physician) can obtain a precise indication of the amountof drugs (number of microbubbles) present at the targeted site. When theoperator decides that the uptake process of the encapsulated drugs inthe neighborhood of the targeted cells is complete, (numeral 99 in FIG.11 designates cells that have taken up the encapsulated drug). Specialligands and vectors can be incorporated on the membrane of themicrobubbles to allow greater specificity to targeted cells.

A preferred embodiment of the apparatus consists of one or moreultrasound heads with one or more ultrasonic sources (or arrays) toallow focusing energy from several different directions. In otherembodiments, in order to allow accurate focusing by the operator,ultrasonic imaging capability can be added, or outside imaginginstrument (MRI, C-arm, etc.) can be used in order to accurately findthe site to be targeted, and focus the ultrasonic waves on it.

Although embodiments of the invention have been described by way ofillustration, it will be understood that the invention may be carriedout with many variations, modifications, and adaptations, withoutdeparting from its spirit or exceeding the scope of the claims.

1. A method for neutralizing acoustically active particles immersed in aflowing fluid, in which: (a) ultrasonic waves are provided, whichpropagate through said fluid, said ultrasonic waves pushing saidparticles in the direction of a friction layer near a surface orsurfaces in contact with said fluid or pushing said particles againstthe direction of flow of said fluid, thereby causing the motion of saidparticles to stop; said ultrasonic waves additionally causing saidparticles to be held in place by pushing them against said surface orsurfaces or against the flow of said flowing fluid; and (b) an acousticradiation force is provided for neutralizing said ultrasonically activeparticles which have been stopped and held in place; characterized inthat, said acoustically active particles are neutralized within theflowing fluid by one or a combination of the following processes: i. adeformation process; wherein an acoustic field is provided which ismodulated at a frequency corresponding to a deformation frequency ofsaid acoustically active particles, thereby surrounding said particleswith an asymmetric acoustic radiation force and causing fragmentation ofsaid particles into smaller ones; and ii. a diffusion process; wherein apulsating acoustic radiation field is provided which alternatelycompresses and releases said particles, thereby increasing theefficiency of the diffusion of material from the interior of saidparticle to the surrounding fluid.
 2. A method according to claim 1,wherein the acoustic radiation force for pushing and the acousticradiation force for neutralizing are provided by the same source.
 3. Amethod according to claim 1, wherein the acoustic radiation force forpushing and the acoustic radiation force for neutralizing are providedby different sources.
 4. A method according to clam 1, wherein theacoustic radiation force for pushing and the acoustic radiation forcefor neutralizing are applied as a superimposition of acoustic radiationforces having two or more frequencies and or waveforms.
 5. A methodaccording to claim 1, wherein the acoustic radiation force for pushingand the acoustic radiation force for neutralizing have waveforms chosenfrom the group comprising, but not limited to: (a) continuous; and (b)pulsating.
 6. A method according to claim 1, wherein the acousticradiation force for pushing and the acoustic radiation force forneutralizing are aimed towards the surface of a wall of the vesselcontaining the fluid or a surface placed in their path.
 7. A methodaccording to claim 1, wherein the acoustic radiation force for pushingand the acoustic radiation force for neutralizing are aimed in adirection opposite to the direction of flow of the fluid and along theaxis of the vessel through which said fluid flows.
 8. A method accordingto claim 1, wherein the acoustic radiation force for pushing and theacoustic radiation force for neutralizing are focused,
 9. A methodaccording to claim 1, wherein the acoustic radiation force for pushingand/or the acoustic radiation force for neutralizing are generated upondetection of the acoustically active particles by a detector ordetectors.
 10. A method according to claim 9, wherein the detector ischosen from the group comprising, but not limited to: (a) an ultrasonicdetector; and (b) an electro-optic detector.
 11. A method according toclaim 9, wherein the detection is made by detecting ultrasonic energysourced emitted by an ultrasonic transducer, refracted by the particles,and detected by said transducer.
 12. A method according to claim 9,wherein the detection is made by detecting ultrasonic energy emitted byan ultrasonic transducer, refracted by the particles, and detected by adifferent transducer.
 13. A method according to claim 1, wherein theflow of the fluid is through a vessel that is open to view.
 14. A methodaccording to claim 1, wherein the flow of the fluid is through a vesselthat is surrounded by an object and therefore is not open to view.
 15. Amethod according to claim 14, wherein the orientation of the vessel isdetermined with the aid of ultrasonic detectors which detect the flow offluid through said vessel.
 16. A method according to claim 15, whereinthe external object is a human body.
 17. A method according to claim 16wherein the vessel is a blood vessel.
 18. A method according to claim 16wherein the vessel is the carotid artery.
 19. A method according toclaim 1, wherein the surface is one or a plurality of membranes andlarge acoustically active particles break apart into smaller particles,which pass through the openings in said membranes upon impact.
 20. Amethod according to claim 19, wherein the size of the pores in themembranes is between 0.1 μm to 1 mm.
 21. A method according to claim 19wherein the membranes together with the ultrasonic propagating fieldacting on the acoustically active particles effectively act as asemi-permeable membrane which permits particles to leave the fluid flowthrough the pores of said membranes and prevents the particles fromreentering the flow by means of: the ultrasonic force alone, as a resultof the merger of the smaller bubbles that have passed through theopenings in said membrane resulting in a bubble that is larger than saidopenings, or by a combination of both effects.
 22. A method according toclaim 19, wherein there is an array of open cells on the side of themembrane surface opposite to the flow of the acoustically activeparticles and wherein after particles are broken apart and pass throughthe openings of said membrane, they enter said cells thus preventingthem from recombining to form particles whose dimensions exceed that ofsaid cells.
 23. A method according to claim 1, wherein the surfacecomprises an array of cells arranged in a honeycomb pattern.
 24. Amethod according to claim 19, wherein the acoustic pressure exerted onacoustically active particles that are larger than the pore size of themembrane causes them to deform without breaking apart upon impact withsaid membrane and slip through said pores, regaining their origin shapeafter slipping through said membrane.
 25. A method according to claim 19where the dimensions of the pores of each succeeding membrane in aplurality of membranes become smaller in the direction of the fluidflow.
 26. A method according to claim 1, wherein the acoustically activeparticles comprise an encapsulated material.
 27. A method according toclaim 26, wherein the encapsulated material is a drug.
 28. An ultrasonicsystem for using the method of claim 1 to neutralize acoustically activeparticles immersed in a flowing fluid, said apparatus comprising: (a) afluid flow path through a vessel; (b) a surface which creates a frictionlayer to the fluid that flows adjacent to it, and can be partially orfully submerged in the fluid, or may consist of a wall of said vessel ora type of membrane; (c) transducing means acoustically connected to saidvessel or submerged in it, said transducing means delivering ultrasonicwaves that propagate through said fluid, said ultrasonic waves pushingsaid particles in the direction of said friction layer near a surface orsurfaces in contact with said fluid or pushing said particles againstthe direction of flow of said fluid; wherein said transducing means areadditionally capable of delivering one or more of the types of acousticradiation fields selected from the following group: (i) a pulsatingacoustic radiation field, which alternately compresses and releases saidparticles; and (ii) an acoustic field which is modulated at a frequencycorresponding to a deformation frequency of said acoustically activeparticles.
 29. A system according to claim 28, wherein the surface is alayer of the flowing fluid and the acoustic energy is directed oppositeto the direction of flow.
 30. A system according to claim 28, whereinthe acoustic energy is focused.
 31. A system according to claim 29,wherein the fluid flows in a tube.
 32. A system according to claim 28,wherein the transducing means comprise an ultrasound head comprising oneor more ultrasound transducers.
 33. A system according to claim 32,wherein the number of ultrasound transducers is at least three and twoof said transducers are used to detect the presence of acousticallyactive particles and to influence the operation of the remainder of saidtransducers.
 34. A system according to 32, wherein the transducing meansare comprised of a disc shaped main transducer surrounded by an outerring shaped transducer, said outer transducer being driven in ananti-phase manner to said main transducer.
 35. A system according toclaim 82, wherein the acoustic energy is focused.
 36. A system accordingto claim 32, wherein the acoustic energy is unfocused.
 37. A systemaccording to claim 28, wherein the system comprises means for providingultrasonic energy for selectively stopping, breaking apart, shrinking,and dissolving acoustically active particles immersed in blood flowingin the carotid arteries.
 38. A system according to claim 37, furthercomprising a disposable pillow.
 39. A system according to claim 37,wherein the system comprises two ultrasonic heads one located on eachcarotid artery.
 40. A system according to claim 37, comprising twoultrasonic heads each comprising at least two ultrasonic bubbledetectors for detect acoustically active particles and/or fluid flow andat least one ultrasonic transducer to provide the ultrasonic energy. 41.A system according to claim 28, wherein the surface is a membrane or hasa honeycomb structure to aid in breaking apart and/or holding theacoustically active particles.
 42. A system according to claim 41,wherein the membrane acting together with the acoustic energyeffectively acts as a semi-permeable membrane, which acts to removeacoustically active particles from the flowing fluid in which they areimmersed.
 43. A system according to claim 28, wherein the vessel throughwhich the fluid flows is an arterial line of cardiopulmonary machine,contrast media catheter, or dialysis machine or a high-flow venous line.44. A system according to claim 28, wherein the acoustically activeparticles comprise encapsulated material.
 45. A system according toclaim 44, wherein the acoustically active particles are delivered to aselected location in a vessel by the flowing fluid, concentrated at saidlocation within said vessel and the encapsulated material is released atsaid location by shrinking and/or breaking apart and/or dissolving saidparticles.
 46. A system according to claim 45, wherein the acousticallyactive particles are introduced into the flowing fluid using a speciallydesigned balloon catheter.
 47. A system according to claim 44, whereinthe encapsulated material is a drug.
 48. A system according to claim 45,wherein the vessel is part of the vascular system of a human or animalbody.